The sodium pump (Na,K-ATPase), a heterodimer consisting of an alpha and a beta-subunit, regulates sodium and potassium homeostasis in mammalian cells and plays a central role in kidney functions. Well- differentiated epithelial cells with distinct apical and basolateral plasma membrane domains separated by tight junctions express high levels of beta subunit. We have shown that the beta-subunit expression is highly reduced in renal clear cell carcinoma, one of the most invasive forms of renal cancer. Subsequently, we showed that in poorly differentiated transformed kidney carcinoma cell lines repletion of beta-subunit expression reduced their motility and induced a well-differentiated phenotype indicating that beta-subunit expression is important to maintain the well-differentiated phenotype of epithelial cells. Further studies indicated a striking correlation between beta-subunit and E-cadherin expression in poorly differentiated carcinoma cell lines. E-cadherin is a cell adhesion molecule implicated in cell adhesion, maintenance of the polarized epithelial phenotype, and invasion suppression of carcinoma cells. Molecular mechanisms leading to the down regulation of E-cadherin also resulted in the down regulation of beta-subunit indicating that a functional synergism between E-cadherin and beta-subunit is involved in the maintenance of the well- differentiated phenotype of epithelial cells. We provide evidence that repletion of beta-subunit expression in highly motile kidney carcinoma cell lines reduces their motility and tumorigenic potential. In this proposal, we shall test the hypothesis that beta-subunit functions as a cell-cell adhesion molecule with its normal level essential to maintain the well-differentiated phenotype of epithelial cells and that reduced levels are associated with the poorly differentiated phenotype and tumorigenicity of carcinoma cells. These studies will ultimately elucidate that Na,K-ATPase beta-subunit is a multifunctional protein and has a crucial role in maintaining the well-differentiated phenotype of epithelial cells independent of its role in the ion transport activity of Na,K-ATPase.